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Social Cognition is Associated with Anterior Insula Volume in Patients with Frontotemporal Dementia
Abstract
Frontotemporal dementia (FTD) is a neurodegenerative disease impacting 50% of people with dementia under the age of 60. A core feature of FTD is a deficit in social cognition. The salience network, a functionally connected assembly of brain regions including the anterior insula (aINS) and anterior cingulate, is impacted by FTD. The Genetic FTD Initiative (GENFI) participants (n=949, females=520, males=429, mean age=48.75 +/- 14 years) includes patients and family members with FTD-associated pathogenic mutations. Baseline analyses showed lower volume of the aINS and lower social cognitive functioning in symptomatic mutation carriers compared to both presymptomatic and healthy controls. In FTD patients, aINS volume was correlated with social cognition scores (r=0.36, p<0.01). Future research mapping the longitudinal relationship between social cognition and the salience network may provide novel insights into FTD onset and progression to expand treatment windows for improved intervention outcomes.
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Background
Population-based prevalence and incidence studies are essential for understanding the burden of frontotemporal dementia (FTD).
Methods
The MEDLINE and EMBASE databases were searched to identify population-based publications from 1985 to 2012, addressing the incidence and/or prevalence of FTD. References of included articles and prior systematic reviews were searched for additional studies. Two reviewers screened all abstracts and full-text reviews, abstracted data and performed quality assessments.
Results
Twenty-six studies were included. Methodological limitations led to wide ranges in the estimates for prevalence (point prevalence 0.01-4.6 per 1000 persons; period prevalence 0.16-31.04 per 1000 persons) and incidence (0.0-0.3 per 1000 person-years). FTD accounted for an average of 2.7% (range 0-9.1%) of all dementia cases among prevalence studies that included subjects 65 and older compared to 10.2% (range 2.8-15.7%) in studies restricted to those aged less than 65. The cumulative numbers of male (373 [52.5%]) and female (338 [47.5%]) cases from studies reporting this information were nearly equal (
p
=0.18). The behavioural variant FTD (bvFTD) was almost four times as common as the primary progressive aphasias.
Conclusions
Population-based estimates for the epidemiology of FTD varied widely in the included studies. Refinements in the diagnostic process, possibly by the use of validated biomarkers or limiting case ascertainment to specialty services, are needed to obtain more precise estimates of the prevalence and incidence of FTD.
Background:
Frontotemporal dementia is a highly heritable neurodegenerative disorder. In about a third of patients, the disease is caused by autosomal dominant genetic mutations usually in one of three genes: progranulin (GRN), microtubule-associated protein tau (MAPT), or chromosome 9 open reading frame 72 (C9orf72). Findings from studies of other genetic dementias have shown neuroimaging and cognitive changes before symptoms onset, and we aimed to identify whether such changes could be shown in frontotemporal dementia.
Methods:
We recruited participants to this multicentre study who either were known carriers of a pathogenic mutation in GRN, MAPT, or C9orf72, or were at risk of carrying a mutation because a first-degree relative was a known symptomatic carrier. We calculated time to expected onset as the difference between age at assessment and mean age at onset within the family. Participants underwent a standardised clinical assessment and neuropsychological battery. We did MRI and generated cortical and subcortical volumes using a parcellation of the volumetric T1-weighted scan. We used linear mixed-effects models to examine whether the association of neuropsychology and imaging measures with time to expected onset of symptoms differed between mutation carriers and non-carriers.
Findings:
Between Jan 30, 2012, and Sept 15, 2013, we recruited participants from 11 research sites in the UK, Italy, the Netherlands, Sweden, and Canada. We analysed data from 220 participants: 118 mutation carriers (40 symptomatic and 78 asymptomatic) and 102 non-carriers. For neuropsychology measures, we noted the earliest significant differences between mutation carriers and non-carriers 5 years before expected onset, when differences were significant for all measures except for tests of immediate recall and verbal fluency. We noted the largest Z score differences between carriers and non-carriers 5 years before expected onset in tests of naming (Boston Naming Test -0·7; SE 0·3) and executive function (Trail Making Test Part B, Digit Span backwards, and Digit Symbol Task, all -0·5, SE 0·2). For imaging measures, we noted differences earliest for the insula (at 10 years before expected symptom onset, mean volume as a percentage of total intracranial volume was 0·80% in mutation carriers and 0·84% in non-carriers; difference -0·04, SE 0·02) followed by the temporal lobe (at 10 years before expected symptom onset, mean volume as a percentage of total intracranial volume 8·1% in mutation carriers and 8·3% in non-carriers; difference -0·2, SE 0·1).
Interpretation:
Structural imaging and cognitive changes can be identified 5-10 years before expected onset of symptoms in asymptomatic adults at risk of genetic frontotemporal dementia. These findings could help to define biomarkers that can stage presymptomatic disease and track disease progression, which will be important for future therapeutic trials.
Funding:
Centres of Excellence in Neurodegeneration.
Behavioural variant of frontotemporal dementia (bvFTD) is a neurodegenerative disease that is clinically characterised by progressive behavioural changes and social interpersonal dysfunctions. Its diagnosis remains a clinical challenge, and depression is one of the main causes of misdiagnoses due to the prevalence of apathy in bvFTD.
To evaluate the sensitivity and specificity of the Social Cognition and Emotional Assessment (SEA) and the mini-SEA for differentiating bvFTD from major depressive disorder (MDD).
Scores for the SEA and mini-SEA for 37 patients with bvFTD (divided into subgroups of 17 with early bvFTD and 20 with moderate bvFTD according to the normal range of the Mattis Dementia Rating Scale), 19 MDD patients and 30 control subjects were compared to define the discrimination power of these tools compared with other standard neuropsychological tests.
SEA and mini-SEA scores were significantly lower for both the early and moderate bvFTD groups compared with control subjects and the MDD group, and very few scores overlapped between patients in the bvFTD subgroups and patients in the MDD and control subgroups. SEA and mini-SEA scores distinguished early bvFTD from MDD with sensitivity and specificity rates above 94%.
Unlike standard executive neuropsychological tests, SEA and the mini-SEA can differentiate MDD from bvFTD in the early stages of the disease. The mini-SEA is an easy tool that can be utilised in neurological or psychiatric departments.
Based on the recent literature and collective experience, an international consortium developed revised guidelines for the diagnosis of behavioural variant frontotemporal dementia. The validation process retrospectively reviewed clinical records and compared the sensitivity of proposed and earlier criteria in a multi-site sample of patients with pathologically verified frontotemporal lobar degeneration. According to the revised criteria, 'possible' behavioural variant frontotemporal dementia requires three of six clinically discriminating features (disinhibition, apathy/inertia, loss of sympathy/empathy, perseverative/ compulsive behaviours, hyperorality and dysexecutive neuropsychological profile). 'Probable' behavioural variant frontotemporal dementia adds functional disability and characteristic neuroimaging, while behavioural variant frontotemporal dementia 'with definite frontotemporal lobar degeneration' requires histopathological confirmation or a pathogenic mutation. Sixteen brain banks contributed cases meeting histopathological criteria for frontotemporal lobar degeneration and a clinical diagnosis of behavioural variant frontotemporal dementia, Alzheimer's disease, dementia with Lewy bodies or vascular dementia at presentation. Cases with predominant primary progressive aphasia or extra-pyramidal syndromes were excluded. In these autopsy-confirmed cases, an experienced neurologist or psychiatrist ascertained clinical features necessary for making a diagnosis according to previous and proposed criteria at presentation. Of 137 cases where features were available for both proposed and previously established criteria, 118 (86%) met 'possible' criteria, and 104 (76%) met criteria for 'probable' behavioural variant frontotemporal dementia. In contrast, 72 cases (53%) met previously established criteria for the syndrome (P 5 0.001 for comparison with 'possible' and 'probable' criteria). Patients who failed to meet revised criteria were significantly older and most had atypical presentations with marked memory impairment. In conclusion, the revised criteria for behavioural variant fronto-temporal dementia improve diagnostic accuracy compared with previously established criteria in a sample with known fronto-temporal lobar degeneration. Greater sensitivity of the proposed criteria may reflect the optimized diagnostic features, less restrictive exclusion features and a flexible structure that accommodates different initial clinical presentations. Future studies will be needed to establish the reliability and specificity of these revised diagnostic guidelines.
The brain is constantly bombarded by stimuli, and the relative salience of these inputs determines which are more likely to capture attention. A brain system known as the 'salience network', with key nodes in the insular cortices, has a central role in the detection of behaviourally relevant stimuli and the coordination of neural resources. Emerging evidence suggests that atypical engagement of specific subdivisions of the insula within the salience network is a feature of many neuropsychiatric disorders.
Compared to late-onset dementias, early-onset dementias (EODs) may have greater focal cognitive involvement with differences in frontal-executive compared to posterior-perceptual deficits.
This study evaluated whether mental status screening based on this frontal-posterior axis can distinguish EODs. Methods: Twenty-three patients each with early-onset Alzheimer's disease (eAD), frontotemporal dementia (FTD), or subcortical ischemic vascular disease (SIVD), and 20 normal controls underwent the Frontal Assessment Battery (FAB) and the Perceptual Assessment Battery (PAB).
Compared to controls, SIVD and FTD groups were impaired on the FAB whereas eAD and SIVD groups were impaired on the PAB. The FAB/PAB ratio further differentiated the groups (F(3,85) = 26.49, P < .001). For sensitivities and specificities of 93%, a cut-off score of 1.25 on the FAB/PAB distinguished eAD, and a cut-off of 0.83 distinguishing FTD.
Although preliminary, this study indicates that mental status screening based on frontal versus posterior cortical functions may help clinicians diagnose EODs.
The molecular neuroscience revolution has begun to rekindle interest in fundamental neuroanatomy. Blending these disciplines may prove critical to our understanding of neurodegenerative diseases, which target specific anatomical systems. Recent research on frontotemporal dementia highlights the potential value of these approaches.
The behavioral variant of frontotemporal dementia leads to progressive social-emotional processing deficits accompanied by anterior cingulate and frontal insular degeneration. These sites form a discrete human neural network and feature a class of layer 5b projection neurons, von Economo neurons, found only in large-brained, socially complex mammals. von Economo neurons have been shown to represent an early target in the behavioral variant of frontotemporal dementia but not in Alzheimer's disease.
Integrative approaches to selective vulnerability may help clarify neurodegenerative disease pathogenesis.